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Hepatic ischemia reperfusion (IR) injury (IRI) occurs during liver transplantation, hepatectomy, and hemorrhagic shock. Oleanolic acid (OA) is a natural compound with antioxidant and anti-inflammatory activity that has been used to treat liver disorders in clinical practice for several years. Here, we investigated the effects and underlying mechanisms of OA in hepatic IRI. A 60-minute partial (70%) hepatic, warm, ischemic reperfusion model was established in BALB/c mice, and two doses (30 and 60 mg/kg) of OA were administered intragastrically for 7 consecutive days prior to hepatic IR. Orbital blood and liver specimens were collected at 2, 8, and 24 h after IR. The results showed that OA preconditioning significantly alleviated hepatic injury, as evidenced by decreased alanine aminotransferase and aspartate aminotransferase levels; improved histology, inhibition of JNK phosphorylation, and high mobility group box 1 (HMGB1); and tumor necrosis factor- α downregulation in hepatic IR mice. OA upregulated Bcl-2 and downregulated caspase-3, caspase-9, Bax, Beclin 1, and LC3, which play crucial roles in the regulation of apoptosis and autophagy. These findings highlighted the protective effects of OA against hepatic IRI mediated by the inhibition of apoptosis and autophagy and the release of HMGB1, which acted as a late inflammatory mediator in hepatic IRI.

Objective: The goal of this study was to determine the effects of beraprost sodium (BPS) preconditioning on hepatic ischemia-reperfusion (IR) injury and its underlying mechanisms of action., Materials and Methods: Mice were randomly divided into sham, IR, IR+BPS (50 µg/kg), and IR+BPS (100 µg/kg) groups. Saline or BPS was given to the mice by daily gavage for 1 week before the hepatic IR model was established. Liver tissues and orbital blood were collected at 2, 8, and 24 hours after reperfusion for the determination of liver enzymes, inflammatory mediators, apoptosis- and autophagy-related proteins, key proteins in P38 and c-Jun N-terminal kinase (JNK) cascades, and evaluation of liver histopathology., Results: BPS preconditioning effectively reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, improved pathological damage, ameliorated production of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and affected expressions of Bax, Bcl-2, Caspase-3, Caspase-8, and Caspase-9, microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, and P62. The protective effects of BPS preconditioning were associated with reduced P38 and JNK phosphorylation., Conclusion: BPS preconditioning ameliorated hepatic IR injury by suppressing inflammation, apoptosis, and autophagy, partially via inhibiting activation of the P38 and JNK cascades., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Methyl jasmonate has recently been found to have anti-cancer activity. Methyl jasmonate detached hexokinase 2 from a voltage dependent anion channel causing a reduction in mitochondrial transmembrane potential that led to the release of cytochrome C and apoptosis inducing factor resulting in intrinsic apoptosis. Blocked adenosine triphosphate synthesis caused by mitochondrial injury hampered oxidative phosphorylation and led to cell necrosis. The results were applied to the in vivo treatment of nude mice with a satisfactory effect. Collectively, our results suggest that methyl jasmonate may be an adjuvant therapy for liver tumors due to its mechanism in cancer cells compared to that in normal cells: The major function is to inhibit glycolysis instead of changing aerobic metabolism.

Ischemia-reperfusion injury (IRI) contributes to liver damage in many clinical situations, such as liver resection and liver transplantation. In the present study, we investigated the effects of the antioxidant, anti-inflammatory, and anticancer agent salidroside (Sal) on hepatic IRI in mice. The mice were randomly divided into six groups: normal control, Sham, Sal (20 mg/kg), IRI, IRI + Sal (10 mg/kg), and IRI + Sal (20 mg/kg). We measured liver enzymes, proinflammatory cytokines, TNF-α and interleukin-6, and apoptosis- and autophagy-related marker proteins at 2, 8, and 24 hours after reperfusion. Components of mitogen-activated protein kinase (MAPK) signaling, including P-38, jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK), were also measured using an MAPK activator anisomycin to deduce their roles in hepatic IRI. Our results show that Sal safely protects hepatocytes from IRI by reducing levels of liver enzymes in the serum. These findings were confirmed by histopathology. We concluded that Sal protects hepatocytes from IRI partly by inhibiting the activation of MAPK signaling, including the phosphorylation of P38, JNK, and ERK. This ameliorates inflammatory reactions, apoptosis, and autophagy in the mouse liver., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Hepatic ischemia-reperfusion (I/R) injury is a common clinical impairment that occurs in many circumstances and leads to poor prognosis. Both apoptosis and autophagy have been shown to contribute to cell death in hepatic I/R injury. 15-Deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ2) is one of the best-studied anti-inflammatory prostaglandins, which has been verified to exert anti-inflammatory and cell-protective functions in various types of cells and animal models. In this study we explored the effects of 15d-PGJ2 on both apoptosis and autophagy in mouse hepatic I/R injury and its possible mechanisms. A model of segmental (70%) hepatic warm ischemia was established in Balb/c mice, and the pathological changes in serum and liver tissues were detected at 6, 12, and 24 h post-surgery, while 15d-PGJ2 (2.5, 7.5, 15 μg, iv) was administered 30 min prior the surgery. Pretreatment with 15d-PGJ2 (7.5, 15 μg) significantly ameliorated I/R-induced hepatic injury evidenced by dose-dependent reduction of serum ALT and AST levels as well as alleviated tissue damages. 15d-PGJ2 pretreatment significantly decreased the serum TNF-α and IL-1β levels and the hepatic expression of F4/80, a major biomarker of macrophages. 15d-PGJ2 pretreatment upregulated the Bcl-2/Bax ratio, thus reducing the number of apoptotic cells in the livers. 15d-PGJ2 pretreatment considerably suppressed the expression of Beclin-1 and LC3, thus decreasing the number of autophagosomes in the livers. Furthermore, 15d-PGJ2 pretreatment activated Nrf2 and inhibited a ROS/HIF1α/BNIP3 pathway in the livers. Pretreatment with the PPARγ receptor blocker GW9662 (2 μg, ip) partly reversed the protective effects of 15d-PGJ2 on hepatic I/R injury. In conclusion, our results confirm the protective effect of 15d-PGJ2 on hepatic I/R injury, an effect that may rely on a reduction in the activation of Kupffer cells and on activation of the Nrf2 pathway, which lead to inhibition of ROS generation, apoptosis, and autophagy.

Glycolysis, as an altered cancer cell-intrinsic metabolism, is an essential hallmark of cancer. Phosphofructokinase (PFK) is a metabolic sensor in the glycolytic pathway, and restricting the substrate availability for this enzyme has been researched extensively as a target for chemotherapy. In the present study, we investigated that the effects of epigallocatechin-3-gallate (EGCG), an active component of green tea, on inhibiting cell growth and inducing apoptosis by promoting a metabolic shift away from glycolysis in aerobic glycolytic hepatocellular carcinoma (HCC) cells. EGCG modulated the oligomeric structure of PFK, potentially leading to metabolic stress associated apoptosis and suggesting that EGCG acts by directly suppressing PFK activity. A PFK activity inhibitor enhanced the effect, while the allosteric activator reversed EGCG-induced HCC cell death. PFK siRNA knockdown-induced apoptosis was not reversed by the activator. EGCG enhanced the effect of sorafenib on cell growth inhibition in both aerobic glycolytic HCC cells and in a xenograft mouse model. The present study suggests a potential role for EGCG as an adjuvant in cancer therapy, which merits further investigation at the clinical level.

Context: We recently reported that F2, an oligomer procyanidin fraction isolated from grape seeds, triggered an original form of cell death in U-87 human glioblastoma cells with a phenotype resembling morphological characteristics of paraptosis. However, the specific death mode induced by F2 and the mechanism of its action have not been assessed so far., Objective: In the present work, we therefore further investigated the death mode of human glioblastoma cells induced by F2 and gained insight into the nature of the signaling pathways activated by F2 in glioblastoma cells., Materials and Methods: Cell viability assay using MTT, (AO/EB) double staining, Western blot analysis, and Ca2+ assay using fura-2., Results: Morphology studies revealed extensive cytoplasmic vacuolization in dying cells and no apoptotic body formation, membrane bleb formation, or nuclear fragmentation, though some was accompanied by MAPK activation and new protein synthesis, and was independent of caspase activation. Moreover, we demonstrated the involvement of calcium mobilization in F2-induced U-87 cell signaling., Discussion and Conclusion: Altogether we showed that F2 induced a kind of cell death resembling paraptosis in U-87 cells. The current report complements previous studies on the characterization of F2-induced U-87 cell death, enhances our understanding of the action mechanism of F2 on glioma, and helps in the development of novel antitumor therapeutics.

Background: GBM astrocytes may adopt fetal astrocyte transcriptomic signatures involved in brain development and migration programs to facilitate diffuse tumor infiltration. Our previous data show that ETS variant 6 (ETV6) is highly expressed in human GBM and fetal astrocytes compared to normal mature astrocytes. We hypothesized that ETV6 played a role in GBM tumor progression. Methods: Expression of ETV6 was first examined in two American and three Chinese tissue microarrays. The correlation between ETV6 staining intensity and patient survival was calculated, followed by validation using public databases—TCGA and REMBRANDT. The effect of ETV6 knockdown on glioma cell proliferation (EdU), viability (AnnexinV labeling), clonogenic growth (colony formation), and migration/invasion (transwell assays) in GBM cells was tested. RNA sequencing and Western blot were performed to elucidate the underlying molecular mechanisms. Results: ETV6 was highly expressed in GBM and associated with an unfavorable prognosis. ETV6 silencing in glioma cells led to increased apoptosis or decreased proliferation, clonogenicity, migration, and invasion. RNA-Seq-based gene expression and pathway analyses revealed that ETV6 knockdown in U251 cells led to the upregulation of genes involved in extracellular matrix organization, NF-κB signaling, TNF-mediated signaling, and the downregulation of genes in the regulation of cell motility, cell proliferation, PI3K-AKT signaling, and the Ras pathway. The downregulation of the PI3K-AKT and Ras-MAPK pathways were further validated by immunoblotting. Conclusion: Our findings suggested that ETV6 was highly expressed in GBM and its high expression correlated with poor survival. ETV6 silencing decreased an aggressive in vitro phenotype probably via the PI3K-AKT and Ras-MAPK pathways. The study encourages further investigation of ETV6 as a potential therapeutic target of GBM.

Tuberculosis (TB), as one of the leading causes of death, poses a serious predicament to the world. MicroRNAs (miRNAs) play a role in the post-transcriptional regulation of gene expression. It has been reported that the expression of miRNAs changes upon mycobacterial infection; the screening and identification of miRNAs regulating the expression of genes could benefit our understanding of TB pathogenesis and generate effective strategies for its control and prevention. In this study, luciferase assays showed that miR-4687-5p is bound to the 3′-untranslated region of natural resistance-associated macrophage protein 1 (NRAMP1). Additionally, we found a significant increase in miR-4687-5p expression in Mycobacterium tuberculosis (Mtb)-infected A549 cells. Concomitantly, we detected a reduced level of NRAMP1 expression, suggesting that NRAMP1 is one of the targets of miR-4687-5p. Infection experiments evidenced that the transfection of miR-4687-5p induced a decrease in NRAMP1 expression and increased intracellular Mtb loads post-infection, indicating that miR-4687-5p promotes the intracellular survival of Mtb through its downregulation of the NRAMP1 protein level. We also found that the transfection of miR-4687-5p induced increased apoptosis and decreased cell proliferation post-infection with Mtb. The results presented in our study suggest that miR-4687-5p may be indicative of the susceptibility of Mtb infection to humans and could act as a potential therapeutic target for tuberculosis treatment. [ABSTRACT FROM AUTHOR]

Background: GBM astrocytes may adopt fetal astrocyte transcriptomic signatures involved in brain development and migration programs to facilitate diffuse tumor infiltration. Our previous data show that ETS variant 6 (ETV6) is highly expressed in human GBM and fetal astrocytes compared to normal mature astrocytes. We hypothesized that ETV6 played a role in GBM tumor progression. Methods: Expression of ETV6 was first examined in two American and three Chinese tissue microarrays. The correlation between ETV6 staining intensity and patient survival was calculated, followed by validation using public databases—TCGA and REMBRANDT. The effect of ETV6 knockdown on glioma cell proliferation (EdU), viability (AnnexinV labeling), clonogenic growth (colony formation), and migration/invasion (transwell assays) in GBM cells was tested. RNA sequencing and Western blot were performed to elucidate the underlying molecular mechanisms. Results: ETV6 was highly expressed in GBM and associated with an unfavorable prognosis. ETV6 silencing in glioma cells led to increased apoptosis or decreased proliferation, clonogenicity, migration, and invasion. RNA-Seq-based gene expression and pathway analyses revealed that ETV6 knockdown in U251 cells led to the upregulation of genes involved in extracellular matrix organization, NF-κB signaling, TNF-mediated signaling, and the downregulation of genes in the regulation of cell motility, cell proliferation, PI3K-AKT signaling, and the Ras pathway. The downregulation of the PI3K-AKT and Ras-MAPK pathways were further validated by immunoblotting. Conclusion: Our findings suggested that ETV6 was highly expressed in GBM and its high expression correlated with poor survival. ETV6 silencing decreased an aggressive in vitro phenotype probably via the PI3K-AKT and Ras-MAPK pathways. The study encourages further investigation of ETV6 as a potential therapeutic target of GBM. [ABSTRACT FROM AUTHOR]

Hepatic ischemia and reperfusion injury is characterized by hepatocyte apoptosis, impaired autophagy, and oxidative stress. Fenofibrate, a commonly used antilipidemic drug, has been verified to exert hepatic protective effects in other cells and animal models. The purpose of this study was to identify the function of fenofibrate on mouse hepatic IR injury and discuss the possible mechanisms. A segmental (70%) hepatic warm ischemia model was established in Balb/c mice. Serum and liver tissue samples were collected for detecting pathological changes at 2, 8, and 24 h after reperfusion, while fenofibrate (50 mg/kg, 100 mg/kg) was injected intraperitoneally 1 hour prior to surgery. Compared to the IR group, pretreatment of FF could reduce the inflammatory response and inhibit apoptosis and autophagy. Furthermore, fenofibrate can activate PPAR-α, which is associated with the phosphorylation of AMPK. [ABSTRACT FROM AUTHOR]

Background: Juglone is a natural pigment, which has a cytotoxic effect against tumor cells. However, its cytotoxicity to human breast cancer cells (Michigan Cancer Foundation-7 [MCF7]) has not been demonstrated. Objective: The objective was to observe the effect of Juglone on the protein expression of caspase-3, 9 in the apoptosis of Human Breast Cancer Cells (MCF7) and apoptosis-related protein, Bcl-2-associated X protein (Bax), and B-cell lymphoma-2 (Bcl-2) and investigate in the inhibitory effect of MCF7. Materials and Methods: Methyl thiazolyl tetrazolium experiment was performed for the detection of the cell growth inhibition effect of MCF7. The apoptosis rate was detected by flow cytometry. Western Blot was used to detect the protein expression of Bax, Bcl-2, and caspase. The messenger RNA (mRNA) was tested using quantitative real-time polymerase chain reaction. Results: Juglone inhibited the growth of MCF7 cells in a concentration- and time-dependent manner and promotes the apoptosis of MCF7 cells in a concentration-dependent manner. Compared with control group, the Juglone group raised the expression of Bax protein (*P < 0.05), and the protein expression of Bcl-2 was decreased (*P < 0.05). The expression of caspase-3 protein was not changed, and the caspase-9 was significantly elevated in the high concentration of Juglone. Cleaved caspase-3, -9 protein was significantly raised (*P < 0.05). The mRNA levels of Bax, caspase-3, and caspase-9 in MCF7 cells of Juglone group were significantly increased compared with control, while the expression of Bcl-2 was suppressed obviously. Conclusion: Juglone inhibited the growth of MCF7 cells and promotes the apoptosis of MCF7 cells. Its mechanism in promoting MCF7 cell apoptosis may be related to the decrease of the expression of the mitochondrial pathway-associated apoptosis factor Bcl-2, increase of the protein expression of Bax, and mitochondrial pathway downstream caspase-3, 9. [ABSTRACT FROM AUTHOR]

Objective: Hepatocellular carcinima is one of the most common tumors in clinic and also one of the leading causes of death from cancer worldwide. Quercetin shows significant effects on blocking the development of various cancers. Methods: We used the human hepatocellular carcinoma LM3 and nude mice tumor model to assess the effects of quercetin in hepatocellular carcinoma and clarify its mechanism of action. We collected LM3 cell line treated with different doses of quercetin at different time periods and determined the vital indexes. The liver tissues of mice were collected and used for western boltting (WB), Hematoxylin and Eosin (H&E) and TUNEL staining. Results: Results indicated that quercetin suppressed the Hepatocellular carcinoma (HCC) growth both in vivo and in vitro. Quercetin could disturb LM3 cells proliferation and cell cycle distribution, thus inducing apoptosis. At the same time, quercetin inhibited LM3 cells migration and invasion and promoted HCC autophagy. These effects at least partly depended on the down‐regulation of the activation of JAK2 and STAT3 by quercetin. Conclusion: Quercetin inhibited hepatocellular carcinoma progression by modulating cell apoptosis, migration, invasion, and autophagy; and its effects were at least partly related with the JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Aims. Levo-tetrahydropalmatine (L-THP) is an active ingredient of Corydalis yanhusuo W. T. Wang, which has many bioactive properties. Herein, we investigated the protective effects of L-THP on concanavalin A- (ConA-) induced hepatitis in mice and explored its possible mechanisms of these effects. Main Methods. Balb/c mice were intravenously injected with 25 mg/kg ConA to generate a model of acute autoimmune hepatitis, and L-THP (20 or 40 mg/kg) was administered orally once daily for 5 d before the ConA injection. The liver enzyme levels, proinflammatory cytokine levels, and other marker protein levels were determined 2, 8, and 24 h after ConA injection. Results. L-THP could decrease serum liver enzymes and pathological damage by reducing the release of inflammatory factors like IL-6 and TNF-α. The results of Western Blot and PCR indicated that L-THP could ameliorate liver cell apoptosis and autophagy. L-THP could suppress T lymphocyte proliferation and the production of TNF-α and IL-6 induced by ConA in a dose-dependent manner in vitro. Additionally, the protective functions of L-THP depended on downregulating TRAF6/JNK signaling. Conclusion. The present study indicated that L-THP attenuated acute liver injury in ConA-induced autoimmune hepatitis by inhibiting apoptosis and autophagy via the TRAF6/JNK pathway. [ABSTRACT FROM AUTHOR]

Salidroside (Sal) is a glycoside extract from Rhodiola rosea L. with anti-inflammatory, antioxidant, anticancer and cardioprotective properties. The present study explored the protective effects and the possible mechanisms of Sal on concanavalin A (ConA)-induced liver injury in mice. Balb/C mice were divided into five groups: Normal control (injected with normal saline), ConA (25 mg/kg), Sal (10 mg/kg) +ConA, Sal (20 mg/kg) + ConA (Sal injected 2 h prior to ConA injection) and Sal (20 mg/kg) only. The serum levels of liver enzymes, pro-inflammatory cytokines, and apoptosis- and autophagy-associated marker proteins were determined at 2, 8 and 24 h after ConA injection. LY294002 was further used to verify whether the phosphoinositide 3-kinase (PI3K)/Akt pathway was activated. Primary hepatocytes were isolated to verify the effect of Sal in vitro. The results indicated that Sal was a safe agent to reduce pathological damage and serum liver enzymes in ConA-induced liver injury. Sal suppressed inflammatory reactions in serum and liver tissues, and activated the PI3K/Akt signaling pathway to inhibit apoptosis and autophagy in vivo and in vitro, which could be reversed by LY294002. In conclusion, Sal attenuated ConA-induced liver injury by modulating PI3K/Akt pathway-mediated apoptosis and autophagy in mice. [ABSTRACT FROM AUTHOR]

Background. Hepatic ischemia reperfusion (IR) injury is a common phenomenon in transplantation or trauma. The aim of the present study was to determine the protective effect of quercetin (QE) on hepatic IR injury via the ERK/NF-κB pathway. Methods. Mice were randomized into the sham, IR, QE100 + IR, and QE200 + IR groups. Quercetin was administered intragastrically daily at two doses (100 mg/kg and 200 mg/kg) for 5 days prior to IR injury. The expression levels of liver enzymes, inflammatory cytokines, and other marker proteins were determined at 2, 8, and 24 hours after IR. And they were compared among these groups. Results. Compared with the IR group, the treatment of QE reduced the release of cytokines, leading to inhibition of apoptosis and autophagy via downregulation of the ERK/NF-κB pathway in this model of hepatic IR injury. Conclusion. Apoptosis and autophagy caused by hepatic IR injury were inhibited by QE following a reduction in the release of inflammatory cytokines, and the relationship between the two may be associated with inactivation of the ERK/NF-κB pathway. [ABSTRACT FROM AUTHOR]

Proanthocyanidins (PAs) belong to the condensed tannin subfamily of natural flavonoids. Recent studies have shown that the main bioactive compounds of Pinus massoniana bark extract (PMBE) are PAs, especially the proanthocyanidins B series, which play important roles in cell cycle arrest, apoptosis induction and migration inhibition of cancer cells in vivo and in vitro. PA-Bs are mixtures of oligomers and polymers composed of flavan-3-ol, and the relationship between their structure and corresponding biomedical potentials is summarized in this paper. The hydroxyl at certain positions or the linkage between different carbon atoms of different rings determines or affects their anti-oxidant and free radical scavenging bioactivities. The degree of polymerization and the water solubility of the reaction system also influence their biomedical potential. Taken together, PMBE has a promising future in clinical drug development as a candidate anticancer drug and as a food additive to prevent tumorigenesis. We hope this review will encourage interested researchers to conduct further preclinical and clinical studies to evaluate the anticancer activities of PMBE, its active constituents and their derivatives. [ABSTRACT FROM AUTHOR]

A series of phenylpiperazine derivatives ( 3a – 3q ) were designed and synthesized. In vitro assays indicated that several phenylpiperazine derivatives had excellent antiproliferative properties against four cancer cell lines including multidrug-resistant cancer cell lines, with IC 50 values in the low micromolar range. The average IC 50 of the most active compound 3b is 0.024 μM to the MCF-7 cell line. In addition, the mechanism of action of these new analogues was investigated by molecular docking studies, insulin-like growth factor 1-receptor (IGF-1R) kinase assay and apoptosis induced assay. These studies confirmed that these new phenylpiperazine derivatives maintain their mechanisms of action by disrupting IGF-1R kinase. [ABSTRACT FROM AUTHOR]

• Apoptosis and autophagy play an important role on HIRI. • Cafestol could efficiently attenuate hepatic ischemia reperfusion injury in mice. • The protective mechanism of cafestol is inhibiting ERK/PPARγ pathway. The study was aimed to explore the hepatocellular protective functions of cafestol during hepatic ischemia-reperfusion injury and the possible mechanisms. Ninety male Balb/c mice were randomly divided into seven groups, including normal control group, L-cafestol(20mg/kg) group, H-cafestol(40mg/kg) group, sham group, IR group, L-cafestol(20mg/kg) + IR group, H-cafestol(40mg/kg) + IR group. Serum liver enzymes (ALT, AST), inflammation mediators, proteins associated with apoptosis and autophagy, indicators linked with ERK/PPARγ pathway, and liver histopathology were measured using ELISA, qRT-PCR, immunohistochemical staining, and western blotting at 2, 8, and 24 hours after reperfusion. Our findings confirmed that cafestol preconditioning groups could reduce the levels of ALT and AST, alleviate liver pathological damage, suppress the release of inflammation mediators, inhibit the production of pro-apoptosis protein including caspase-3, caspase-9 and Bax, decrease the expression of autophagy-linked protein including Beclin-1 and LC3, increase anti-apoptosis protein Bcl-2, and restrain the activation of ERK and PPARγ. Cafestol preconditioning could attenuate inflammatory response, apoptosis and autophagy on hepatic ischemia reperfusion injury by suppressing ERK/PPARγ pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] • 51 artemyrianolide H derivatives were synthesized and evaluated for cytotoxicity against human hepatoma cells. • 34 compounds were more active than artemyrianolide H and sorafenib. • Compound 25 induced G2/M phase arrest, apoptosis and bound to PDGFRA and MAP2K2. Artemyrianolide H (AH) is a germacrene-type sesquiterpenolid isolated from Artemisia myriantha , and showed potent cytotoxicity against three human hepatocellular carcinoma cell lines HepG2, Huh7, and SK-Hep-1 with IC 50 values of 10.9, 7.2, and 11.9 µM, respectively. To reveal structure−activity relationship, 51 artemyrianolide H derivatives including 19 dimeric analogs were designed, synthesized, and assayed for their cytotoxicity against three human hepatoma cell lines. Among them, 34 compounds were more active than artemyrianolide H and sorafenib on the three cell lines. Especially, compound 25 exhibited the most promising activity with IC 50 values of 0.7 (HepG2), 0.6 (Huh7), and 1.3 µM (SK-Hep-1), which were 15.5, 12.0, and 9.2-fold higher than that of AH and 16.4, 16.3 and 17.5-fold higher than that of sorafenib. Cytotoxicity evaluation on normal human liver cell lines (THLE-2) demonstrated good safety profile of compound 25 with SI of 1.9 (HepG2), 2.2 (Huh 7) and 1.0 (SK-Hep1). Further studies revealed that compound 25 dose-dependently arrested cells at G2/M phase which was correlated with the up-regulation of both cyclin B1 and p-CDK1, and induced apoptosis through the activation of mitochondrial pathways in HepG2 cells. In addition, the migratory and invasive abilities in HepG2 cells after treatment with 1.5 μM of compound 25 were decreased by 89% and 86% with the increase of E-cadherin expression accompanied by the decrease of N-cadherin, vimentin expression. Bioinformatics analysis based on machine learning predicted that PDGFRA and MAP2K2 might be acting targets of compound 25 , and SPR assays demonstrated compound 25 were bound with PDGFRA and MAP2K2 with K D value of 0.168 nM, and 8.49 µM, respectively. This investigation proposed that compound 25 might be considered as a promising lead compound for the development of antihepatoma candidate. [ABSTRACT FROM AUTHOR]

Abstract Background Hepatic ischemia/reperfusion (IR) injury is a common medical phenomenon that occurs during a number of clinical conditions, such as liver transplantation, severe injuries, and shock. In our study, we determined the protective functions of levo-tetrahydropalmatine (L-THP) on hepatic IR injury in mice by inhibiting the ERK/NF-κB signaling pathway. Method BALB/c mice were randomly divided into six groups as follows: normal control (NC); sham; L-THP (40 mg/kg); IR; L-THP (20 mg/kg) + IR; and L-THP (40 mg/kg) + IR. Liver tissues and sera were collected at three time points after reperfusion (2, 8, and 24 h). The liver enzyme, inflammatory factor, and other protein levels in the serum and liver tissues were detected. Results L-THP pretreatment alleviated hepatocyte injury caused by IR and reduced the production of proinflammatory cytokines, such as IL-6 and TNF-α. Furthermore, L-THP could inhibit the ERK/NF-κB signaling pathway to attenuate hepatocyte apoptosis and autophagy. And the protective effect of L-THP is positively correlated with its dose. Conclusion L-THP protects the liver from IR injury by inhibiting the release of inflammatory factors and alleviating liver cell apoptosis and autophagy. The protective functions of L-THP may be partly based on the downregulation of the ERK/NF-κB pathway. [ABSTRACT FROM AUTHOR]

Isorhamnetin, a flavonoid compound extracted from plants’ fruit or leaves, like sea buckthorn (Hippophae rhamnoides L.), has many biological functions, including anti-tumor, anti-oxidant and anti-inflammatory effect. The present study is in order to explore the hepatoprotective effect of isorhamnetin on concanavalin A (ConA)-induced acute fulminant hepatitis and the underlying mechanism. Mice were injected with ConA (25 mg/kg) to induce acute fulminant hepatitis, three doses of isorhamnetin (10/30/90 mg/kg) was intraperitoneally administrated about 1 h previously. The serum and liver tissues were harvested at 2, 8, and 24 h after ConA injection. The levels of serum liver enzymes and proinflammatory cytokines were significantly reduced in isorhamnetin administration groups. Besides, isorhamnetin improved pathological damage. Furthermore, isorhamnetin affected P38/PPAR-α pathway, and subsequently regulated the expression of apoptosis and autophagy related proteins. The present study investigated that isorhamnetin inhibits apoptosis and autophagy via P38/PPAR-α pathway in mice. [ABSTRACT FROM AUTHOR]

Quercetin, as a member of the flavonoids family, has many beneficial properties. The aim of our study was to evaluate the protective effect of quercetin in ConA-induced hepatitis in mice, and to clarify its mechanism of action. Hepatitis was induced by using ConA (25 mg/kg), and quercetin was administered intragastrically at the dose of 100 mg/kg or 200 mg/kg for 5 days before ConA injection. The serum levels of liver enzymes, inflammatory cytokines and other marker proteins were determined at 2 h, 8 h and 24 h after ConA injection. Following ConA injection, serum levels of liver enzymes and inflammatory cytokines were significantly increased. Quercetin ameliorated liver damage and histopathological changes, and suppressed the release of inflammatory cytokines. The expression of Bax, Bcl-2, Beclin-1, LC3, P62 and caspase 9 were markedly affected by quercetin pretreatment. The expression of TRAF6 and p-JNK were decreased in the quercetin groups. Quercetin attenuated apoptosis and autophagy in ConA-induced autoimmune hepatitis by inhibiting TRAF6/JNK pathway. [ABSTRACT FROM AUTHOR]

Aims Propylene glycol alginate sodium sulfate (PSS), a sulfated polysaccharide possesses anti-inflammatory effects. Here, we investigated the effect of PSS on concanavalin A (Con A)-induced liver injury in mice and examined the underlying mechanisms. Main methods Balb/C mice were injected intravenously with Con A (25 mg/kg) to generate a model of acute liver injury. PSS (25 or 50 mg/kg) was injected intraperitoneally 1 h before the Con A administration. The levels of serum liver enzymes, inflammatory cytokines, and other marker proteins were determined, and liver injury was assessed histopathologically 2, 8, and 24 h after Con A injection. Key findings Pretreatment with PSS reduced the levels of serum liver enzymes, inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and attenuated histopathological damage in Con A-induced liver injury in mice. The effects of Con A were mediated by apoptosis and autophagy, as indicated by changes in protein and gene expression of related factors after Con A injection. PSS activated the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway and showed a protective function against apoptosis and autophagy. Significance PSS ameliorated Con A-induced liver injury by downregulating inflammatory cytokines including TNF-α and IL-1β and regulating apoptosis and autophagy via the PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]